Mood disorders, such as depressive disorders and bipolar disorder, are serious health burdens affecting approximately 10% of the population. Bipolar disorder is estimated to affect 1.6% of the population, whereas major depressive disorder (MDD) is estimated to have a lifetime prevalence in the general population of between 10% and 25% for women and from 5% to 12% for men. The World Health Organization predicts the MDD will be the second greatest contributor to the global burden of disease by 2020.
Although the symptoms of MDD are frequently experienced by most individuals, clinical depression is different in that feelings of unhappiness and disappointment become quantitatively different, pervasive or interfere with normal function (Doris A et al., 1999, Lancet 354:1369-1375). The Diagnostic and Statistic Manual, version IV (DSM-IV) describes an individual as having major depressive episode when five or more of the following symptoms are present nearly everyday for a two week period: 1) depressed mood most of the day; 2) markedly diminished interest or pleasure in all, or almost all, activities most of the day; 3) significant weight loss when not dieting or weight gain, or decrease or increase in appetite; 4) insomnia or hypersomnia; 5) psychomotor agitation or retardation; 6) fatigue or loss of energy; 7) feelings of worthlessness or excessive or inappropriate guilt; 8) diminished ability to think or concentrate or indecisiveness; and 9) recurrent thoughts of death (DSM-IV, 1994).
The hypothesis that mood disorders have a biological component has been studied since the 1960's. The catecholamine and indoleamine hypotheses of mood disorders were first proposed in the mid-1960's in two separate reviews (Coppen A, 1967, Br J Psychiatry 113: 1237-1264; Schildkraut J J, Am. J. Psychiatry 122:509-522). The catecholamine theory of mood disorders proposed that depression resulted from decreased norepinephrine and mania was the result of elevated norepinephrine levels at central adrenergic receptor sites (Schildkraut J J, supra). The indoleamine hypothesis was derived from evidence suggesting that serotonin (5-HT) was responsible for the disorders, specifically, decreased 5-HT levels caused depression (Coppen, supra).
Interest in norepinephrine and 5-HT as important neurotransmitters in mental illness arose when subjects given the tranquilizing substance reserpine, known to deplete brain amine levels, displayed profound behavioural depression during the course of treatment (Coppen, supra; Peterfy G et al., 1976, Psychoneuroendocrinology I:243-253; Quetsch R M et al., 1959, Circulation 19: 366-375). A study by Lingjaerde (1963, Acta Psychiatr Scand 39(Suppl 170): 1-109) reported similar findings when subjects were administered tetrabenazine, a compound with similar amine depleting effects. Clinical studies measuring peripheral levels of 5-HT and norepinephrine metabolites, 5-HIAA and MHPG respectively, have been conducted in an attempt to support the catecholamine and indoleamine hypotheses. Peripheral measures in psychiatric illnesses are the preferred way to obtain information on mood state-dependent changes associated with the disorders. However, results from several studies suggest that peripheral measures of 5-HT and norepinephrine metabolism from plasma, urine and cerebrospinal fluid (CSF) are inconsistent and fail to provide any evidence to support the catecholamine and indoleamine hypotheses (Geracioti Jr T D et al., 1997, Depress Anxiety 6:89-94; Placidi G P et al., 2001, Biol Psychiatry 50: 783-791 and references therein).
Strong evidence to support the catecholamine and indoleamine hypotheses has come from studies examining the mechanism of action of antidepressants. Most antidepressants have been developed to target one or more of the elements involved in the reuptake, synthesis and/or catabolism of norepinephrine or 5-HT. The result of chronic treatment with any of these drugs is increased synaptic concentrations of 5-HT or norepinephrine, suggesting that the pathophysiology of MDD involves decreased CNS levels of these neurotransmitters. However, the primary synthetic or catabolic component responsible for the increase in synaptic concentrations of 5-HT or norepinephrine remains elusive.
Monoamine oxidase-A (MAO-A) is an enzyme that metabolizes 5-HT, norepinephrine and dopamine in the brain. It is the main route for metabolism of 5-HT, and an important route of metabolism for the other two monoamines. All three of these monoamines are high affinity substrates for MAO-A (Fowler C et al., Substrate-Selective Interaction Between Monoamine Oxidase and Oxygen. In: Singer T, Von Korff R, Murphy D, eds. Monoamine Oxidase: Structure, Function and Altered Functions. New York: Academic Press, Inc.; 1979:145-151; Kinemuchi H et al., Substrate Specificities of the Two Forms of Monoamine Oxidase. In: Tipton K, Dostert P, Strolin-Benedetti M, eds. Monoamine Oxidase and Disease: Prospects for Therapy with Reversible Inhibitors. New York: Academic Press, Inc.; 1984:53-62; Schoepp D D et al., 1981, J Neurochem 36(6):2025-2031; White H et al., Characterization of Multiple Substrate Binding Sites of MAO. In: Singer T, Von Korff R, Murphy D, eds. Monoamine Oxidase: Structure, Function and Altered Functions. New York: Academic Press, Inc.; 1979:145-151; Houslay M D et al., 1974, Biochem J 139(3):645-652). MAO-A has been detected in cells that release these monoamines, with the highest levels in norepinephrine releasing neurons (Konradi C et al., 1988, Neuroscience 26(3):791-802; Luque J M et al., 1995, J Comp Neurol 363(4):665-680; Saura J et al., 1996, Neuroscience 70(3):755-774; Konradi C et al., 1989, Neuroscience 33(2):383-400; and Moll G et al., 1990, J Neural Transm Suppl 32:67-77) (MAO-A in cells that release monoamines and MAO-A in cells that do not release monoamines are both believed to contribute to monoamine metabolism (Youdim M B et al., 2006, Nat Rev Neurosci 7(4):295-309)). Medications that inhibit MAO-A, and MAO-A knockout models are associated with greater levels of extracellular 5-HT in prefrontal cortex, hippocampus, and superior raphe nuclei, norepinephrine in prefrontal cortex and hippocampus, and dopamine in striatum. In brain, the predominant location for this enzyme is on the outer mitochondrial membranes in neurons (Saura J et al., supra). Monoamine oxidase-A density is highest in locus coeruleus, moderate in the cortex, hippocampus, and striatum, low in cerebellar cortex and minimal in white matter (S aura J et al., supra; and S aura et al., 1992, J Neurosci 12(5):1977-1999). Brain MAO-A density is highly correlated with MAO-A activity (Saura et al., ibid).
Previous studies have shown brain MAO-A levels are elevated in patients with MDD. For example, a recent study measured an index of MAO-A density in 17 major depressive episode (MDE) subjects (secondary to MDD) and 17 healthy subjects with [11C] harmine PET. The subjects were otherwise healthy. Depressed subjects were drug free for at least five months although most were antidepressants naïve. Depressed subjects were aged 18-50, met DSM-IV diagnosis of current MDE and MDD verified by SCID for DSM-IV, and a psychiatric consultation, non-smoking and had greater than 17 on the 17 item HDRS. The index of MAO-A binding was highly significantly elevated (p<0.001) in each region, with an average magnitude 34 percent (or two standard deviations) in the depressed subjects (Meyer et al., 2006, Arch Gen Psychiatry 63(11):1209-1216). The study by Meyer et al., shows that brain MAO-A is elevated in early onset depression (prior to age 40) because the magnitude was large, the sample was carefully defined, the method was selective for brain MAO-A and there has never previously been a post mortem study of brain MAO-A levels in medication free depressed subjects (Meyer et al., 2008, Semin Nucl Med 38(4):287-304). Previous post mortem studies of MAO-A did not examine the question as to whether MAO-A is elevated in medication free, early onset depression. The most reasons are lack of specificity for MAO-A, diagnostic non-specificity by sampling of suicide victims rather than depressed suicide victims, inclusion of subjects who recently took medication, and/or overdosed, no differentiation between early onset depression and late onset depression, and small sample size. The results seen with MAO-A levels in brain have been replicated by Meyer et al., (2009, Arch Gen Psych 66:1304-12). In addition, Johnson et al., (2011, Neuropsychopharmacology 36:2139-48) reported greater MAO-A density during MDE applying immunoblotting techniques in post-mortem prefrontal cortex.
Since imaging the brain during a MDE is technically challenging and slightly impractical in the clinical setting, a peripheral measure correlating the increase in MAO-A levels in the brain to MDD is desired. However, peripheral and central measures, such as the brain, do not always correlate. For example, platelet 5-HT2A receptor density does not correlate with regional brain 5-HT2A density (Cho R et al., 1999, Neurosci Lett 261(3):139-142). Moreover, as mentioned above, inconsistent results have been obtained when monoamine metabolite levels are measured in blood in an effort to correlate with disease state. These results seem at odds to the behavioural patterns of subjects depleted of certain brain monoamines. The ability to measure the increase in MAO-A levels seen in the brain, using blood, for example, is desired.